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Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterised by reduced or absent OTC enzyme activity, resulting in the accumulation of neurotoxic ammonia. Approximately 80%-90% of the causative variants are identified by Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA) of the OTC gene. A 23-year-old male with biochemical evidence of OTCD was referred for molecular analysis. Initial Sanger sequencing yielded no pathogenic variants. MLPA testing raised suspicion of a mosaic deletion of exon 1; however, high-resolution microarray did not identify a copy number variant on the X chromosome. Sequencing over the suspected breakpoint detected a hemizygous likely pathogenic promoter variant, c.-106C > A, which was located within the MLPA probe binding site. Subsequently, historical patients referred to our centre, without a molecular aetiology for their OTCD, were re-sequenced with these primers and this variant was also identified in two additional unrelated males. All three patients described in this case series have the late-onset disease. Two presented at 5 years of age with vomiting, whilst the other was managed from birth based on a family history of late-onset OTCD. One patient required liver transplantation due to recurrent decompensations; the other two are managed with a protein-restricted diet. All three patients have not sustained any significant neurological insults and are functioning well as adults. These cases support screening of the promoter region within the OTC gene, particularly if a molecular basis has not been elucidated by MLPA or sequencing of the coding regions.
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PURPOSE: To describe and compare the systemic and ocular findings in two siblings with mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome), one treated with recombinant galsulfase, and one who was untreated. METHOD: One female patient aged 33 years (case 1) who had received galsulfase enzyme replacement therapy for 11 years, and her younger male sibling by 3 years (case 2), who had declined systemic treatment, underwent clinical ophthalmic examination and retinal ocular coherence tomography. The female sibling underwent electrophysiology testing of visual function. RESULTS: Case 1 had best corrected visual acuity right 6/4.8 and left 6/6. Case 2 had best corrected visual acuity of 6/6 in each eye. Case 1 had bilateral mild corneal haze and a clinically unremarkable posterior segment examination. Case 2 had bilateral very mild corneal haze and retinal striae on examination. Ocular coherence tomography showed choroidal folds at the maculae in both patients, more pronounced in Case 2, who also had retinal folds and epiretinal membrane. Electroretinography showed very mild involvement of the rods only in Case 1. CONCLUSION: These two siblings with mucopolysaccharidosis type VI, one treated and one untreated, displayed variable levels of systemic, corneal, and chorioretinal involvement in their disease Further studies of choroidal changes in MPS VI may prove useful as a biomarker of ocular response to treatment outside the blood-retina barrier. Both patients have provided written consent to publish case details.
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Opacidad de la Córnea , Mucopolisacaridosis VI , Córnea , Terapia de Reemplazo Enzimático/métodos , Femenino , Humanos , Masculino , Mucopolisacaridosis VI/diagnóstico , Mucopolisacaridosis VI/tratamiento farmacológico , HermanosRESUMEN
Purpose: To report novel retinal findings in two male patients with mucopolysaccharidosis type II (Hunter syndrome) receiving long-term human recombinant idursulfase enzyme replacement therapy.Method: Two males aged 19 and 26 years who had received enzyme replacement therapy for 12 and 13 years, respectively, with good compliance and no infusion-related reactions, were examined clinically and underwent optical coherence tomographic scanning of the retina and electroretinography testing.Results: Case 1 had visual acuity 20/32 in each eye and case 2 had visual acuity 20/25 in each eye. Both patients had clinically unremarkable anterior segment and fundus examinations. Ocular coherence tomography imaging in both patients showed thickening of the external limiting membrane with hyperreflective material in at least one eye each. One patient had bilateral foveoschisis and the other had mild foveal hypoplasia. Electroretinography showed a negative response in the patient with foveoschisis and reduced amplitudes in the patient with foveal hypoplasia.Conclusions: These two patients with Hunter syndrome receiving idursulfase treatment both have subfoveal deposition of hyperreflective material in the external limiting membrane despite good compliance and tolerance of the standard dose of enzyme therapy for this disorder. One patient has developed foveoschisis and negative electroretinogram suggesting abnormality of inner retinal function. Further studies are needed to determine the nature of the hyperreflective material, as well as the effect of systemic treatment on retinal findings in patients with mucopolysaccharidosis type II.
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Mucopolisacaridosis II/complicaciones , Enfermedades de la Retina/complicaciones , Adulto , Electrorretinografía , Terapia de Reemplazo Enzimático/métodos , Humanos , Iduronato Sulfatasa/uso terapéutico , Masculino , Mucopolisacaridosis II/diagnóstico , Mucopolisacaridosis II/tratamiento farmacológico , Fenotipo , Retina/fisiopatología , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/tratamiento farmacológico , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Adulto JovenRESUMEN
BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase. Untreated, PKU is associated with a wide range of cognitive and psychiatric sequelae. Contemporary management guidelines recommend lifetime dietary control of phenylalanine (Phe) levels, however many individuals who discontinue dietary control subsequently suffer symptoms of anxiety, depression and disturbances to cognition. We undertook a prospective cohort study of patients with early-treated phenylketonuria who had ceased dietary control to test the hypothesis that resumption of dietary control of PKU is associated with improvements in measures of psychiatric morbidity and cognitive functioning. METHODS: We re-initiated dietary control for early-treated patients with PKU and monitored cognitive and psychiatric outcomes over a twelve-month period. Assessments included objective cognitive function (measured by cognitive proficiency index (CPI)), anxiety and depression scales. General linear mixed model (GLMM) analyses were performed to assess change in psychometric variables from baseline over twelve months after resumption of dietary control. RESULTS: A total of nine patients were recruited. Mean age was 33 years (SD = 8.75), five were female. Mean time off dietary control was 19.1 years (SD = 11.3), and mean baseline phenylalanine (Phe) levels were 1108 µmol/L (SD = 293). GLMM analysis demonstrated a positive relationship between CPI and time on diet (b = 0.56 [95% CI = 0.17, 0.95]). Age, time off diet, Phe levels and depression scores were not associated with cognitive function. There was a negative relationship between time on diet and anxiety (b = - 0.88 95% CI = [- 1.26, - 0.50]) and depression ratings (b = - 0.61, 95% CI = [- 0.95, - 0.26]). CONCLUSIONS: This study demonstrated improvements in cognitive function, anxiety, and depression ratings associated with resumption of dietary control of PKU. Raw Phe levels were not strongly associated with psychiatric or cognitive scores in this cohort. These findings support the importance of lifelong treatment for PKU in improving the cognitive and psychiatric sequelae of the disease.
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Fenilalanina Hidroxilasa , Fenilcetonurias , Adulto , Cognición , Femenino , Humanos , Masculino , Fenilalanina , Fenilcetonurias/tratamiento farmacológico , Estudios ProspectivosRESUMEN
The COVID-19 pandemic, which was reported in early January 2020 in China and spread rapidly around the globe, will certainly remain as one of the most impactful disruptive events of the 21st century. To contain the spread of the virus while awaiting a vaccine, countries applied different approaches from simply giving advice on personal hygiene and applying progressive measures to total lockdown. This paper aims to investigate the impacts of the pandemic on travel behavior in Istanbul, Turkey, through a longitudinal panel study conducted in three phases during the early stages of the epidemic and pandemic. The paper reflects the travel behavior evolution during the development of the outbreak resulting from residents' self- regulation and governmental measures, distinguishing travel for commute, Social/Recreational/Leisure (SRL), and shopping activities, as well as use of different travel modes based on various socio-economic characteristics. Due to the application of the social distancing of at least 1.5â¯m, closure of numerous non-essential venues, encouraging teleworking and distance education, job losses and cancellation of all social gatherings in Istanbul between the second and third phase of our data collection, the transition in travel activity pattern and transport mobility appears to be quite extreme, particularly for commuting and SRL trips.
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BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare neurometabolic disorder resulting in a heterogeneous clinical phenotype. Adolescent and adult patients with SSADH deficiency may present with OCD symptoms. There is minimal literature regarding the pathological basis of OCD symptoms and their management amongst SSADH deficiency patients. CASE PRESENTATION: A 26-year-old woman with SSADH deficiency experienced obsessional slowness and hesitancy in her activities of daily living, with motor rituals and stereotypies of her hands and face. Neuroimaging revealed T2 hyperintensities of the globi pallidi bilaterally. Commencement of the serotonergic escitalopram moderately improved her OCD symptoms. The addition of the dopaminergic pramipexole hydrochloride yielded further improvement, following unsuccessful trial of other adjuncts: risperidone, methylphenidate and mirtazapine. CONCLUSIONS: Pallidal pathology may explain the manifestation of OCD symptoms amongst individuals with SSADH deficiency. Serotonergic and concomitant dopaminergic therapy may be a viable treatment regimen for SSADH deficiency patients presenting with OCD symptoms.
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Errores Innatos del Metabolismo de los Aminoácidos , Trastorno Obsesivo Compulsivo , Actividades Cotidianas , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Niño , Discapacidades del Desarrollo , Femenino , Humanos , Trastorno Obsesivo Compulsivo/complicaciones , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Succionato-Semialdehído Deshidrogenasa/deficienciaRESUMEN
Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations in the gene for phenylalanine hydroxylase (PAH). Reduced PAH activity results in significant hyperphenylalaninemia, which leads to alterations in cerebral myelin and protein synthesis, as well as reduced levels of serotonin, dopamine, and noradrenaline in the brain. When untreated, brain development is grossly disrupted and significant intellectual impairment and behavioral disturbance occur. The advent of neonatal heel prick screening has allowed for diagnosis at birth, and the institution of a phenylalanine restricted diet. Dietary treatment, particularly when maintained across neurodevelopment and well into adulthood, has resulted in markedly improved outcomes at a cognitive and psychiatric level for individuals with PKU. However, few individuals can maintain full dietary control lifelong, and even with good control, an elevated risk remains of-in particular-mood, anxiety, and attentional disorders across the lifespan. Increasingly, dietary recommendations focus on maintaining continuous dietary treatment lifelong to optimize psychiatric and cognitive outcomes, although the effect of long-term protein restricted diets on brain function remains unknown. While psychiatric illness is very common in adult PKU populations, very little data exist to guide clinicians on optimal treatment. The advent of new treatments that do not require restrictive dietary management, such as the enzyme therapy Pegvaliase, holds the promise of allowing patients a relatively normal diet alongside optimized mental health and cognitive functioning.
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Mitochondrial diseases are rare, heterogeneous conditions affecting organs dependent on high aerobic metabolism. Presenting symptoms and signs vary depending on the mutation and mutant protein load. Diabetes mellitus is the most common endocrinopathy, and recognition of these patients is important due to its impact on management and screening of family members. In particular, glycemic management differs in these patients: the use of metformin is avoided because of the risk of lactic acidosis. We describe a patient who presented with gradual weight loss and an acute presentation of hyperglycemia complicated by the superior mesenteric artery syndrome. His maternal history of diabetes and deafness and a personal history of hearing impairment led to the diagnosis of a mitochondrial disorder. Learning points: â¢â¢ The constellation of diabetes, multi-organ involvement and maternal inheritance should prompt consideration of a mitochondrial disorder. â¢â¢ Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD) are the most common mitochondrial diabetes disorders caused by a mutation in m.3243A>G in 80% of cases. â¢â¢ Metformin should be avoided due to the risk of lactic acidosis. â¢â¢ There is more rapid progression to insulin therapy and higher prevalence of diabetic complications compared to type 2 diabetes. â¢â¢ Diagnosis of a mitochondrial disorder leads to family screening, education and surveillance for future complications. â¢â¢ Superior mesenteric artery syndrome, an uncommon but important cause of intestinal pseudo-obstruction in cases of significant weight loss, has been reported in MELAS patients.
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PURPOSE: To report retinal findings in two patients with mucopolysaccharidosis type I (MPS I) receiving human recombinant alpha-l-iduronidase (Laronidase) as enzyme replacement therapy. OBSERVATIONS: Patient 1 had visual acuity 20/20 right eye, 20/25 left eye and unremarkable anterior segment and retinal examination. Optical coherence tomography (OCT) scanning demonstrated parafoveal thinning and subfoveal hyperreflectant material. Patient 2 had visual acuity 20/20 both eyes, with dense nuclear cataract both eyes. Retinal examination demonstrated bull's eye maculopathy both eyes. OCT scanning confirmed parafoveal atrophy and demonstrated similar appearing subfoveal hyperreflectant material, more prominent than in case 1. CONCLUSIONS AND IMPORTANCE: These two patients with MPS I receiving Laronidase treatment have developed bull's eye maculopathy changes and subfoveal deposition of hyperreflectant material despite excellent compliance and good tolerance of the standard dose of enzyme therapy for this disorder. Further studies are required to determine the nature of the material, the incidence and the effect of enzyme replacement therapy on these findings in patients with MPS I.
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Enfermedades del Sistema Nervioso/etiología , Trastornos Innatos del Ciclo de la Urea/complicaciones , Urea/metabolismo , Diagnóstico Diferencial , Humanos , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/metabolismo , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/metabolismoRESUMEN
The ferroportin-related disorder is an increasingly recognized cause of hereditary iron overload. Based on the in vitro behavior of different ferroportin mutant subsets, it was suggested that different forms of the disorder might exist in humans. We used MRI to address this question in vivo in 22 patients from four different pedigrees carrying different ferroportin mutations: A77D, N144H, G80S and Val 162del. We found that, based on the iron status of spleen and bone macrophages, two different forms of the disease can be identified: a classic, common form, characterized by hepatocyte, splenic macrophage and bone marrow macrophage iron retention in patients carrying the A77D, G80S and Val 162del ferroportin variants; a rarer non-classic form, associated with liver iron overload but normal spleen and bone marrow iron content in patients with the N144H mutation. The two forms are likely caused by lack- or gain-of-protein function, respectively. Interestingly, in treated patients with the classic form, the spleen and the spine show appreciable iron accumulation even when serum ferritin is normal and liver iron content low. In conclusion, MRI is a useful non-invasive diagnostic tool to categorize and diagnose the disorder, monitor the status of iron depletion and gain insights on its natural history and management.
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Proteínas de Transporte de Catión/genética , Sobrecarga de Hierro/diagnóstico por imagen , Sobrecarga de Hierro/genética , Imagen por Resonancia Magnética , Errores Innatos del Metabolismo de los Metales/diagnóstico por imagen , Errores Innatos del Metabolismo de los Metales/genética , Adolescente , Adulto , Anciano de 80 o más Años , Proteínas de Transporte de Catión/metabolismo , Niño , Femenino , Ferritinas/sangre , Humanos , Hierro/sangre , Sobrecarga de Hierro/sangre , Masculino , Errores Innatos del Metabolismo de los Metales/sangre , Persona de Mediana Edad , Mutación Missense , Radiografía , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/metabolismo , Bazo/diagnóstico por imagen , Bazo/metabolismoRESUMEN
Serum bilirubin is an important antioxidant that is found at increased levels in hereditary hemochromatosis patients. We hypothesized that increased levels of serum bilirubin may play a protective role against oxidative stress induced by iron overload in carriers of mutations in the hereditary hemochromatosis gene (HFE). We studied the relation between serum total bilirubin, serum iron levels, the HFE C282Y and H63D mutations, and mortality. The study was conducted in 2,332 randomly selected subjects from the Rotterdam Study, a population-based follow-up study of people aged 55 years or over. Serum bilirubin levels were significantly correlated with serum iron (Pearson's correlation coefficient (r) = 0.4, P < 0.001), transferrin saturation (r = 0.4, P < 0.001), and serum ferritin (r = 0.2, P < 0.05). Carriers of the HFE mutations had higher levels of bilirubin compared to wild-type homozygotes. The relation was the strongest in H63D heterozygotes or homozygotes and C282Y heterozygotes. High levels of serum bilirubin were associated with a 2.8 (95% CI 0.9-8.8) fold reduction in mortality in H63D homozygotes and a 2.2 (1.0-4.7) fold reduction in mortality in C282Y heterozygotes. Taken together, our data suggest that the high levels of the antioxidant bilirubin may counteract the adverse effect of oxidative stress induced by iron overload. This may explain in part the reduced penetrance of the HFE mutations.
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Bilirrubina/sangre , Antígenos de Histocompatibilidad Clase I/genética , Hierro/sangre , Proteínas de la Membrana/genética , Anciano , Análisis de Varianza , Distribución de Chi-Cuadrado , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Hemocromatosis/sangre , Hemocromatosis/genética , Hemocromatosis/mortalidad , Proteína de la Hemocromatosis , Heterocigoto , Homocigoto , Humanos , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Análisis de Supervivencia , Tasa de Supervivencia , Factores de TiempoRESUMEN
OBJECTIVE: Recent reports warn that the worldwide cell culture capacity is insufficient to fulfill the increasing demand for human protein drugs. Production in milk of transgenic animals is an attractive alternative. Kilogram quantities of product per year can be obtained at relatively low costs, even in small animals such as rabbits. We tested the long-term safety and efficacy of recombinant human -glucosidase (rhAGLU) from rabbit milk for the treatment of the lysosomal storage disorder Pompe disease. The disease occurs with an estimated frequency of 1 in 40,000 and is designated as orphan disease. The classic infantile form leads to death at a median age of 6 to 8 months and is diagnosed by absence of alpha-glucosidase activity and presence of fully deleterious mutations in the alpha-glucosidase gene. Cardiac hypertrophy is characteristically present. Loss of muscle strength prevents infants from achieving developmental milestones such as sitting, standing, and walking. Milder forms of the disease are associated with less severe mutations and partial deficiency of alpha-glucosidase. METHODS: In the beginning of 1999, 4 critically ill patients with infantile Pompe disease (2.5-8 months of age) were enrolled in a single-center open-label study and treated intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week. RESULTS: Genotypes of patients were consistent with the most severe form of Pompe disease. Additional molecular analysis failed to detect processed forms of alpha-glucosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed only a trace amount of the 95-kDa biosynthetic intermediate form in the fourth (patient 1). With the more sensitive detection method, 35S-methionine incorporation, we could detect low-level synthesis of -glucosidase in 3 of the 4 patients (patients 1, 2, and 4) with some posttranslation modification from 110 kDa to 95 kDa in 1 of them (patient 1). One patient (patient 3) remained totally deficient with both detection methods (negative for cross-reactive immunologic material [CRIM negative]). The alpha-glucosidase activity in skeletal muscle and fibroblasts of all 4 patients was below the lower limit of detection (<2% of normal). The rhAGLU was tolerated well by the patients during >3 years of treatment. Anti-rhAGLU immunoglobulin G titers initially increased during the first 20 to 48 weeks of therapy but declined thereafter. There was no consistent difference in antibody formation comparing CRIM-negative with CRIM-positive patients. Muscle alpha-glucosidase activity increased from <2% to 10% to 20% of normal in all patients during the first 12 weeks of treatment with 15 to 20 mg/kg/week. For optimizing the effect, the dose was increased to 40 mg/kg/week. This resulted, 12 weeks later, in normal alpha-glucosidase activity levels, which were maintained until the last measurement in week 72. Importantly, all 4 patients, including the patient without any endogenous alpha-glucosidase (CRIM negative), revealed mature 76- and 70-kDa forms of -glucosidase on Western blot. Conversion of the 110-kDa precursor from milk to mature 76/70-kDa alpha-glucosidase provides evidence that the enzyme is targeted to lysosomes, where this proteolytic processing occurs. At baseline, patients had severe glycogen storage in the quadriceps muscle as revealed by strong periodic acid-Schiff--positive staining and lacework patterns in hematoxylin and eosin--stained tissue sections. The muscle pathology correlated at each time point with severity of signs. Periodic acid-Schiff intensity diminished and number of vacuoles increased during the first 12 weeks of treatment. Twelve weeks after dose elevation, we observed signs of muscle regeneration in 3 of the 4 patients. Obvious improvement of muscular architecture was seen only in the patient who learned to walk. Clinical effects were significant. All patients survived beyond the age of 4 years, whereas untreated patients succumb at a median age of 6 to 8 months. The characteristic cardiac hypertrophy present at start of treatment diminished significantly. The left ventricular mass index decreased from 171 to 599 g/m2 (upper limit of normal 86.6 g/m2 for infants from 0 to 1 year) to 70 to 160 g/m2 during 84 weeks of treatment. In addition, we found a significant change of slope for the diastolic thickness of the left ventricular posterior wall against time at t = 0 for each separate patient. Remarkably, the younger patients (patients 1 and 3) showed no significant respiratory problems during the first 2 years of life. One of the younger patients recovered from a life-threatening bronchiolitis at the age of 1 year without sequelae, despite borderline oxygen saturations at inclusion. At the age of 2, however, she became ventilator dependent after surgical removal of an infected Port-A-Cath. She died at the age of 4 years and 3 months suddenly after a short period of intractable fever of >42 degrees C, unstable blood pressure, and coma. The respiratory course of patient 1 remained uneventful. The 2 older patients, who both were hypercapnic (partial pressure of carbon dioxide: 10.6 and 9.8 kPa; normal range: 4.5-6.8 kPa) at start of treatment, became ventilator dependent before the first infusion (patient 2) and after 10 weeks of therapy (patient 4). Patient 4 was gradually weaned from the ventilator after 1 year of high-dose treatment and was eventually completely ventilator-free for 5 days, but this situation could not be maintained. Currently, both patients are completely ventilator dependent. The most remarkable progress in motor function was seen in the younger patients (patients 1 and 3). They achieved motor milestones that are unmet in infantile Pompe disease. Patient 1 learned to crawl (12 months), walk (16 months), squat (18 months), and climb stairs (22 months), and patient 3 learned to sit unsupported. The Alberta Infant Motor Scale score for patients 2, 3, and 4 remained far below p5. Patient 1 followed the p5 of normal. CONCLUSION: Our study shows that a safe and effective medicine can be produced in the milk of mammals and encourages additional development of enzyme replacement therapy for the several forms of Pompe disease. Restoration of skeletal muscle function and prevention of pulmonary insufficiency require dosing in the range of 20 to 40 mg/kg/week. The effect depends on residual muscle function at the start of treatment. Early start of treatment is required.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Leche/enzimología , Transgenes , alfa-Galactosidasa/uso terapéutico , Animales , Animales Modificados Genéticamente , Cardiomegalia/etiología , Preescolar , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Lactante , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Desempeño Psicomotor , Conejos/genética , Proteínas Recombinantes/uso terapéutico , Insuficiencia Respiratoria/etiología , Análisis de Supervivencia , Resultado del Tratamiento , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismoRESUMEN
Pompe's disease is an autosomal recessive myopathy. The characteristic lysosomal storage of glycogen is caused by acid alpha-glucosidase deficiency. Patients with late-onset Pompe's disease present with progressive muscle weakness also affecting pulmonary function. In search of a treatment, we investigated the feasibility of enzyme replacement therapy with recombinant human alpha-glucosidase from rabbit milk. Three patients (aged 11, 16, and 32 years) were enrolled in the study. They were all wheelchair-bound and two of them were ventilator dependent with a history of deteriorating pulmonary function. After 3 years of treatment with weekly infusions of alpha-glucosidase, the patients had stabilized pulmonary function and reported less fatigue. The youngest and least affected patient showed an impressive improvement of skeletal muscle strength and function. After 72 weeks of treatment, he could walk without support and finally abandoned his wheelchair. Our findings demonstrate that recombinant human alpha-glucosidase from rabbit milk has a therapeutic effect in late-onset Pompe's disease. There is good reason to continue the development of enzyme replacement therapy for Pompe's disease and to explore further the production of human therapeutic proteins in the milk of mammals.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , alfa-Glucosidasas/uso terapéutico , Adolescente , Adulto , Animales , Niño , Femenino , Estudios de Seguimiento , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Modelos Lineales , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Proyectos Piloto , Conejos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , alfa-Glucosidasas/farmacologíaRESUMEN
Hereditary hemochromatosis is classically inherited as a recessive trait but is genetically heterogeneous. Mutations in the HFE and the TFR2 genes account for about 80% of patients and a third locus on chromosome 1q is responsible for juvenile hemochromatosis. We describe here the clinical and biological characteristics of autosomal dominant form of iron overload due to the N144H mutation of the SLC11A3 gene. Clinical signs of iron overload in patients include joint pains, cardiomyopathies, liver fibrosis and hormonal disorders including diabetes mellitus. The main and most common clinical symptoms in this family were joint complaints and early signs of arthrosis. Serum ferritin levels in iron overloaded subjects varied from 31 to 2179 ng/ml and the transferrin saturation from 13 to 88.6%. The iron overload is moderate compared to patients with type 1 hemochromatosis but the deferoxamine test was normal in all patients. The disease in this family segregated as a dominant trait. None of the patients was homozygous or compound heterozygous for any known mutation in the HFE or TFR2 genes. The disease in this family represents a non-classical form of iron overload caused by the N144H mutation in the SLC11A3 gene. The reports of other distinct mutations in SLC11A3 suggest that this gene may be of interest for further etiologic research.